QRS-Based CRT Advantage for Women in Mild HF: Meta-Analysis

June 27, 2014

SILVER SPRING, MD — Women, compared with men, showed improved survival from cardiac resynchronization therapy (CRT) across a wider range of prolonged QRS durations, a key factor in guidelines-based CRT indications, in an analysis based on three major CRT trials of predominantly NYHA class 2 patients[1].

Specifically, in the trials comparing CRT with defibrillator (CRT-D) vs implantable defibrillator without CRT capability, CRT significantly improved outcomes in patients with left bundle-branch block (LBBB) when the baseline QRS duration was at least 130 ms for women and 150 ms for men.

For women with LBBB and a QRS of 130 ms to <150 ms, the risk of heart failure or death fell by 76% (p<0.001) among those randomized to CRT-D vs the other device; the mortality risk on its own also declined 76% (p=0.03). Men in that QRS range with LBBB showed no significant difference for either end point in the analysis, which was based on pooled patient-level data out to three years in the REVERSE , MADIT-CRT , and RAFT trials.

The guidelines reserve their strongest, unqualified class I recommendation for CRT therapy for patients with systolic HF, LBBB, and a QRS duration >150 ms based largely on meta-analyses of trials that enrolled about 80% men, according to the authors of the current analysis, led by Dr Robbert Zusterzeel (US Food and Drug Administration, Silver Spring, MD), writing June 23, 2014 in JAMA Internal Medicine. In those meta-analyses, "it was not possible to perform robust interaction and subgroup analysis by sex and clinical characteristics due to lack of individual-patient data," they write.

The group's findings are consistent with but go beyond several secondary analyses based solely on MADIT-CRT patients that saw a significant CRT-D benefit in women but not men at QRS durations <150 ms, they observe.

"The authors appropriately conclude in [their] adequately powered study that among patients with mild heart failure, women with LBBB benefit from CRT at a shorter QRS duration than men," write Dr C Noel Bairey Merz (Cedars Sinai Heart Institute, Los Angeles, CA) and Dr Vera Regitz-Zagrosek (Charité University Medicine, Berlin, Germany) in an accompanying editorial[2].

"Because the current US guidelines give only a class IIa recommendation (benefit [exceeds] risk, additional studies with focused objectives needed) for patients with QRS duration of 130 to 149 ms, this new finding [from Zusterzeel et al] indicates that this device [CRT] is likely underused in women," they observe.

"These results also shed light on a major contributor to the misdiagnosis and suboptimal treatment of CVD in women: guidelines are typically based on a male standard and do not address important differences in women."

For the current analysis, Zusterzeel et al pooled all 1820 MADIT-CRT patients, 1663 patients who entered RAFT without a pacemaker, and 593 from REVERSE for whom there were adequate QRS data. Of the 4076 patients, 22% were women; 87% of women and 82% of men were in NYHA class 2 heart failure.

Hazard Ratio (95% CI) for CRT-D vs ICD, Clinical Outcomes by QRS Duration in Women vs Men with LBBB in Pooled Analysis

End points Women Men
Baseline QRS 130-149 ms
Heart failure or death 0.24 (0.11–0.53) 0.85 (0.60–1.21)
Death 0.24 (0.06–0.89) 0.86 (0.49–1.52)
Baseline QRS >150 ms
Heart failure or death 0.33 (0.21–0.52) 0.47 (0.37–0.59)
Death 0.36 (0.16–0.82) 0.65 (0.47–0.91)
CRT-D=cardiac resynchronization therapy with defibrillator
ICD=implantable cardioverter-defibrillator without biventricular pacing

In adjusted analyses, a significant advantage for women treated with CRT vs no CRT, in terms of both heart failure or death and death by itself, emerged among those with a baseline QRS 130 ms to 149 ms. Neither women nor men benefited in either end point from CRT at shorter QRS durations, and both groups significantly benefited in both end points at longer QRS durations.

"The fact that women normally have smaller ventricles and shorter QRS duration than men provides an anatomical and/or physiological explanation for the findings, but the higher rate of nonischemic cardiomyopathy in women compared with men [67% vs 33%] may have also contributed," the group writes.

None of the authors of the meta-analysis or the editorial reported conflicts of interest.

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